DEC 20, 2018 10:28 AM PST

Pathophysiology, Diagnosis, and Treatment of Cervical Cancer

WRITTEN BY: Dena Aruta

Cervical cancer is the fourth most common cancer found in women, globally, for incidence (6.6%) and mortality (7.5%). It is highly preventable through the human papillomavirus (HPV) vaccine and routine Pap smear examination.  There are over 270,000 deaths per year from cervical cancer with 85% coming from low-to-middle income countries. Even though there are effective methods to identify precancerous cells using the Pap smear, low-to-middle income countries have been inundated with other competing healthcare priorities including lack of financial resources, ineffective health systems, and few trained clinicians making cervical cancer screening challenging to achieve. According to the Centers for Disease Control (CDC), the U.S. sees approximately 11,900 new cases annually with black and Hispanic women affected more than whites or Asians.

Pathophysiology of the Disease Process in Cervical Cancer

Central to the development of cervical cancer is infection with HPV with the two major risk factors being chronic infection with high-risk HPV (HR HPV) and ineffective clearance of the virus. While 90% of HPV infections in women clear on their own within a few months or years, research has shown that HR HPV modifies genome sequences affecting the woman’s physiology leading to distinct clinical presentations. Cytology exams have shown low-grade squamous intraepithelial lesions up to two years after the clearance of the infection in some women. The process of the transformation of a cell infected with HPV to a cancer cell is very complex and described in basic terms involves the infection of basal cells found “between the squamous epithelium of the ectocervix and the columnar epithelium of the endocervix.". Viral replication occurs within the epithelial cell during its differentiation cycle where genes coding for viral replication factors are dispatched. The differentiation cycle is required for the production of viral particles on the top of the squamous epithelium. Finally, HPV DNA replication begins when the basal cell DNA is duplicated.

HPV Types and Grading

Although there are over 100 HPVs, the eight most common types implicated in cervical cancer include HPV 16, 18, 31, 33, 35, 45, 52, and 58. HPV 16 is responsible for most of the cervical cancers globally. Grading for the progression of cervical cancer includes epithelial tissue described in phases from normal epithelium to cervical intraepithelial neoplasia (CIN) 1-3 and then invasive cervical cancer. Lesions that are diagnosed as CIN grades 2-3 are considered precursors to cervical cancer.

Cofactors Involved

Because such a small portion of women infected with HPV go on to develop invasive cervical cancer, this indicates that there must be other host, viral, and environmental factors allowing for viral persistence and disease progression. The most studied cofactor is tobacco smoking, which has been proven to play a part in cervical cancer, although it is not clear if it is due to immunomodulation or genotoxicity. Oral and injectable hormonal contraceptives have also been shown to increase the risk of cervical cancers as well as an increasing number of pregnancies.

Standards of Practice

As awareness of the burden of cancer among women has become increasingly recognized, practice guidelines have changed to include screening tests and services, which have become an integral part of well-care visits for women. When precancerous or cancerous lesions are detected early, a decrease in mortality, economic costs, and psychological effects for both the individual and her community can be seen. The Breast and Cervical Cancer Mortality Reduction Act authorized the CDC to provide funding, through the National Breast and Cervical Cancer Early Detection Program (NBCCEDP), to agencies in every state for both cervical and breast cancer screening to low-income women, who would otherwise not receive these services. Screening tests include mammograms, Pap smears with or without an HPV test, clinical breast exams, and pelvic exams. If women require additional tests such as breast ultrasound, biopsies, or diagnostic mammograms, they are provided these services promptly.

The American Cancer Society has integrated HPV DNA testing into current clinical practice, which has improved its sensitivity for detecting CIN 2 lesions. They also recommend performing a follow-up test 12 months later or genotyping the lesion for HPV 16 and 18. Having a negative genotyping at a follow-up in 12 months is also suggested. Further examination with colposcopy is recommended for patients positive for HPV 16 and 18, while the other strains can be tested by reflex cytology.

Factors Important for Disease Management

The Breast and Cervical Cancer Treatment Act was passed by Congress in 2000, which “allowed states to use Medicaid services to cover treatment for women diagnosed with pre-cancer or cancer through the NBCCEDP." All states approved the Medicaid waiver to cover cancer treatment by 2003 making services available for women who met their state Medicaid requirements.

The type of pharmacological treatment depends on the stage of cancer. When invasive cancer is detected early, surgery to remove the lesion is usually sufficient. The WHO states that, for precancerous lesions, “the technology of choice is loop electrosurgical excision procedure (LEEP). For settings where LEEP cannot be performed or in low resource settings, recent WHO guidelines recommend cryotherapy as a good alternative treatment for eligible VIA positive lesions." In more advanced and invasive cancers, a combination of surgery and radiation is the standard therapy with the choice of chemotherapy to complement in later stages of the disease. In many low-to-middle income countries, there is not a capacity to provide conventional therapies or patients who have little-to-no access to affordable services. Compliance with treatment is also a considerable challenge because of geographic, financial, and social barriers.

In developing or third-world countries, the lack of resources and services available within the healthcare system affects the physical capacity to manage the disease. These structural incapacities negatively impact the access to services as well as disease outcomes. Women, particularly those living in remote and rural areas, are often unable to access health services due to barriers such as distance, lack of transportation, financial deterrents, and family and work responsibilities. Because of their inability to access screening and treatment services, most of the deaths from cervical cancer are seen in women who live in low-to-middle income countries.

Patient Education

Successful management of cervical cancer involves a comprehensive strategy for education regarding prevention and treatment and benefits from a multidisciplinary approach. A multidisciplinary program utilizes a broad range of essential elements beginning with community education and social mobilization then moving on to vaccination awareness, screening, and treatment of precancerous to cancerous lesions. Palliative care is an important end-stage service. National cervical cancer programs should include education on reproductive health, adolescent health, and cancer control. People should be made aware that the HPV vaccination is not a replacement for cervical cancer screening. Carefully designed materials that are used to promote awareness of the HPV vaccine and infection and cervical cancer are an essential part of educational programs within communities as well as for teachers, parents, adolescents. Communication about the availability of local services and resources needs to be promoted also. When dealing with different countries and cultures, education that incorporates culturally-specific campaigns, social resources, and information about available services should be provided.

Financial Considerations

 Liu et al. analyzed phase-specific costs for cervical cancer encountered by public payers in Canada. The resources that they included in the study were “inpatient hospitalization, emergency department visit, same-day surgery, physician services, prescription drugs, rehabilitation, laboratory services, services from non-physician provider, radiation therapy, chemotherapy, long-term care, home care, and complex continuing care.” Their results showed that during the pre-diagnosis phase the mean total direct costs were $3155. This value increased to $17,938 during the initial treatment phase but then was reduced to $6429 in the continuing period. Once a patient reached the terminal phase, the cost dramatically increased to $58,319. All of these costs were converted into Canadian dollars, where $1.00 CDN = $1.00 USD. Among patients with cervical cancer, physician fees were the highest cost driver in the pre-diagnosis and continuing care phase, and inpatient costs were the highest cost driver during the terminal phase.

 

Cervical cancer continues to be a significant health burden for women in the U.S. as well as globally. Clinicians can begin to reduce these numbers by providing appropriate and timely preventive services and treatments, which are essential to decrease both the morbidity and mortality seen with cervical cancer. The burden of disease is even more significant among certain racial and ethnic groups (blacks, Hispanics) and for women who do not have access to screening and healthcare services. Financial costs can be prohibitive to women who are under or uninsured creating barriers to accessible care. Effective screening, prevention, and disease management require evidence-based recommendations to change and improve procedures, technologies, and education. All women should have access to reproductive care, and emphasis needs to be placed on the eliminating the disparities seen in women who have little-to-no income in both the U.S. and globally.  

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